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Title: Total synthesis of the macrolide core of (+)-spirastrellolide A
Author: Dalby, S. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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Spirastrellolide A is a polyketide metabolite isolated from the Caribbean marine sponge Spirastrella coccinea, which represents a potential lead for the development of novel therapeutic agents for the treatment of cancer as well as various neurological and metabolic disorders. The results and discussion section provides a chronological account of work towards the total synthesis of spirastrellolide A. As part of preliminary studies towards the original structural assignment, the synthesis of the C1-C21 spiroacetal-containing fragment 141 is described first. Subsequent work towards the revised structure for spirastrellolide is then detailed, which led to the synthesis of the diastereomeric C1-C25 ABC fragments 146 and 147. Chapters 5-8 then describe the development and implementation of a revised strategy which culminated in the highly convergent synthesis of spirastrellolide A macrolactone 467, achieved in 1.0% yield over the longest linear sequence of 33 steps. This synthesis exploits a number of effective boron-mediated processes, including highly stereoselective aldol and alkylation methodology and most notably, B-alkyl Suzuki coupling of the advanced intermediates 449 and 349 and the stereoselective installation of the C23 and C24 stereocentres, as part of a double hydroboration process under substrate control. The key fragments 459 and 450 were advanced to BC-spiroacetal 462 employing a mild and highly efficient process for BC-spiroacetalisation, following which a further four steps provided macrolactone 467. Global deprotection of 467 provided the fully elaborated macrolide core of spirastrellolide A, which was in excellent agreement with the natural product data. Completion of the total synthesis finally requires installation of the C41-C47 side-chain.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available